- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00459771
Evaluating the Effect of Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity
Prospective, Randomized, Pharmacological Intervention Study; Evaluating Effect of the Angiotensin II-receptor (AT1) Blocker Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity in Patients Treated With Trastuzumab
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Prospective, randomized pharmacological intervention study
Primary objectives:
- to determine whether concurrent ATII-antagonist treatment can prevent trastuzumab-related cardiotoxicity, defined as a decline in LVEF of more than 15% or a decrease to an absolute value <45%
Secondary objectives:
- To determine if 'Brain Natriuretic Peptide' (NT-proBNP) and troponin T can be used as surrogate marker in the monitoring of trastuzumab-associated cardiotoxicity
- To determine genetic variability in relevant genes such as the HER2 gene (by assessing single nucleotide polymorphisms [SNPs] in the kinase domain) and explore any correlations with trastuzumab induced cardiotoxicity 3) To determine the reversibility of a decrease in left ventricular ejection fraction (LVEF) associated with trastuzumab treatment
Arm I : placebo Arm II : AT1 blocker candesartan (32 mg/day; run in 16 mg during week 1)
Randomization: before chemotherapy treatment period. Study period: chemotherapy period, trastuzumab treatment period 26 weeks follow up after discontinuation of trastuzumab treatment and thereafter 1 month follow-up after end of placebo or AT1 blocker.
Candesartan treatment will start the same day as the first infusion of trastuzumab and will continue up to 26 weeks after the end of treatment with trastuzumab.
Women with primary HER2 positive breast cancer who are considered for adjuvant systemic treatment with anthracycline containing chemotherapy and trastuzumab.
Before start of anthracycline treatment:
- Medical history, physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- Electrocardiogram
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, thyroid stimulating hormone, glucose, cholesterol, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
- Pregnancy test
- Genotype analysis
Every chemotherapy cycle
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, (NT-proBNP, troponin T analysis)
Before start of trastuzumab treatment:
- Physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- Electrocardiogram
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
After 3, 6 and 9 months trastuzumab:
- Physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
After 1 year trastuzumab, 26 weeks after the last trastuzumab administration:
- Physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- Electrocardiogram
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count, serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
The primary endpoint of the study is the deterioration of the cardiac function defined as a decline in LVEF of 15% or more to an absolute value below 45% during the year with trastuzumab.
From previous studies it is estimated that about 30% of the patients treated with trastuzumab will show deterioration of LVEF.
A total of 200 patients will receive trastuzumab and candesartan or trastuzumab and placebo in this double blind placebo-controlled study. The number of patients randomized (= before chemotherapy period) for this trial shall be more than 200 as a small number of patients might drop out before start of therapy with trastuzumab. This number cannot exactly be determined beforehand.
Study Type
Enrollment (Actual)
Phase
- Phase 3
Contacts and Locations
Study Locations
-
-
-
Alkmaar, Netherlands
- Medisch Centrum Alkmaar
-
Almere, Netherlands
- Flevoziekenhuis
-
Amsterdam, Netherlands, 1066 CX
- The Netherlands Cancer Institute
-
Amsterdam, Netherlands
- Onze Lieve Vrouwe Gasthuis
-
Amsterdam, Netherlands
- Slotervaart Hospital
-
Assen, Netherlands
- Wilhelmina Ziekenhuis
-
Den Bosch, Netherlands
- Jeroen Bosch Hospital
-
Deventer, Netherlands
- Deventer Ziekenhuis
-
Enschede, Netherlands
- Medisch Spectrum Twente
-
Groningen, Netherlands
- Martini Ziekenhuis
-
Groningen, Netherlands
- University Medical Center Groningen
-
Heerenveen, Netherlands
- Ziekenhuis De Tjongerschans
-
Leeuwarden, Netherlands
- Medisch Centrum Leeuwarden
-
Nieuwegein, Netherlands
- Antonius Ziekenhuis
-
Nijmegen, Netherlands
- Canisius-Wilhelmina Hospital
-
Nijmegen, Netherlands
- UMC St. Radboud
-
Venlo, Netherlands
- VieCuri Medisch Centrum voor Noord-Limburg
-
Winterswijk, Netherlands
- Streekziekenhuis Koningin Beatrix
-
Zwolle, Netherlands
- Isala Klinieken
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Women aged ≥18 years
- WHO: ≤ 2
- Strongly HER2-positive breast cancer, defined as an immunohistochemistry score of 3+ using the HercepTestTM, or gene amplification by fluorescence in situ hybridization, or chromogenic in situ hybridization (CISH).
- Serum creatinine <140 umol/l or creatinine clearance > 50 ml/min (by Cockcroft-Gault formula)
- Thyroid stimulating hormone between 0.5-3.9 MU/l
- Blood pressure systolic ≥ 140 mmHg and diastolic ≥ 90 mmHg is acceptable at randomization. However prior to the first administration of trastuzumab blood pressure should be regulated and should be systolic ≥ 100 mmHg and ≤ 180 mmHg and diastolic ≥ 60 mmHg and ≤ 100 mmHg. (blood pressure should be regulated according to the guidelines of appendix 5)
- LVEF ³ 50% assessed by multigated angiography (MUGA) or cardiac ultrasound
- Adjuvant regimen: trastuzumab start ≥ 3 weeks after day 1 of the last anthracycline chemotherapy cycle
- Trastuzumab treatment according to standard medical care
- Written informed consent to participate in the study
Exclusion Criteria:
- Prior anthracycline chemotherapy regimen or anti-HER2 therapy, or other prior biologic or immunotherapy for breast cancer treatment or any malignancy
- Previous malignancy requiring chemotherapy or radiotherapy
- Uncontrolled serious concurrent illness
- Patients with New York Heart Association (NYHA) class II/III/IV congestive heart failure
- Myocardial infarction < 6 months before randomization
- Treatment with ACE inhibitor, ATII blocker, or lithium. Patients treated with ACE inhibitor, or ATII blocker can switch (after randomization and during the chemotherapy period) to alternative antihypertensive therapy; see appendix 5.
- History of hypersensitivity to the study medication
- Pregnancy or breast feeding
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
|
Placebo, 32 mg, oral QD
|
Active Comparator: Candesartan
Candasartan
|
AT1 blocker candesartan, 32 mg oral QD
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
The occurrence of cardiotoxicity, defined as a decline in LVEF (MUGA) of more than 15% or a decrease of less than 15% to an absolute value below 45%.
Time Frame: during 1 year trastuzumab therapy and during 26 weeks after discontinuation of trastuzumab
|
during 1 year trastuzumab therapy and during 26 weeks after discontinuation of trastuzumab
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: J.H.M. Schellens, MD PhD, The Netherlands Cancer Institute
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Chemically-Induced Disorders
- Pathologic Processes
- Heart Diseases
- Cardiovascular Diseases
- Wounds and Injuries
- Drug-Related Side Effects and Adverse Reactions
- Radiation Injuries
- Cardiotoxicity
- Molecular Mechanisms of Pharmacological Action
- Antihypertensive Agents
- Angiotensin II Type 1 Receptor Blockers
- Angiotensin Receptor Antagonists
- Candesartan
Other Study ID Numbers
- M06HER
- 2006-001707-11 (EudraCT Number)
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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